PROJECT SUMMARY/ABSTRACT Each of the Project Leaders supported by the proposed Center for Musculoskeletal Disease Research (CMDR) will require the generation of new genetically modified mice or cell lines to accomplish the goals of their proposed studies. To serve the needs of this COBRE, a Genetic Models Core will be created by expanding an existing transgenic mouse facility at the University of Arkansas for Medical Sciences (UAMS). This existing facility has a strong record of producing transgenic mice. However, to meet the needs of the proposed CMDR, it will be necessary to expand its capabilities by adding new technologies and personnel. This will be accomplished in part using recently developed tools that are based on the CRISPR-Cas9 system to provide gene-editing services in both mice and cell lines. This expansion of services will create a Genetic Models Core that, in addition to meeting the needs of the COBRE Project Leaders, will provide new cutting-edge services to the research communities at UAMS, its affiliated institutions, and across Arkansas. In Specific Aim 1, we propose to provide state-of-the-art services for the generation and maintenance of genetically modified mice. Generation services will include the design and creation of transgenic and gene-targeted mice by pronuclear injection. Maintenance services will include sperm cryopreservation, in vitro fertilization, and strain rederivation. In Specific Aim 2, we propose to develop new approaches and services that support genetic model creation and use. New services needed by CMDR members, such as creation of genetically modified cell lines, will be developed. In addition, Core personnel will continuously update gene-editing tools for cell and mouse modification via evaluation of current literature and attendance at workshops and meetings. In Specific Aim 3, we propose to provide training and education related to the use of genetic models. Project Leaders and other users will be trained to efficiently and accurately produce experimental cohorts of genetically modified mice, and we will educate users on potential problems that are often encountered with the use of such models. Core personnel will also educate the research communities at UAMS and other campuses in Arkansas, about the services and technologies available through the Genetic Models Core. The scientific theme of the proposed CMDR is that conditions that lead to deterioration of the skeleton have a molecular basis whose identification will guide development of specific and effective therapies. The Genetic Models Core is consistent with this theme in that it will allow Project Leaders to rapidly and efficiently test the role of specific molecular changes in pathological processes the affect the skeleton or in which the skeleton plays a major role, such as myeloma or breast cancer metastases.